Field of the Invention
The present invention is focused on the fields of immunotherapy and HIV/AIDS therapeutics. The invention directs a cell product that simultaneously targets multiple HIV antigens while remaining immune to the virus, the method used to generate this product, and its use in preventing and treating active and latent HIV infection, as well as HIV-associated malignancies. More specifically, the invention discloses a method for generation and ex vivo expansion of HIV-antigen specific T-cells that are treated or modified to decrease or eliminate expression of mannosyl-oligosacharide glucosidase enzyme (MOGS) thus rendering them resistant to infection by HIV.
Description of Related Art
Antiretroviral therapy (ART) prolongs the life of HIV-infected individuals by preventing the progression to severe immunodeficiency but ART cannot cure infection, and lifelong therapy is necessary to provide continuous viral suppression. Populations that are at high risk for treatment non-adherence are vulnerable to drug resistance and further transmission of HIV, preventing the eradication of the virus on a global scale. Furthermore, the long-term use of ART can lead to side effects in the renal, hepatic, and cardiovascular systems [1]. Another reason why HIV continues to be a pandemic is the lack of an effective vaccine. The most successful vaccine trial to date only produced a marginally statistically significant efficacy of 31% for HIV prevention [2].
T-cells have been used to treat virus-associated cancers and viral reactivations post-transplant [3-7]. Although T-cells specific for HIV antigens have been produced, CD4+ T-cells are susceptible to infection by HIV which enters the cell through a CD4-dependent mechanism.
The mannosyl-oligosacharide glucosidase (MOGS) enzyme is deficient in a disease called congenital disorder of glycosylation type IIb (CDG-IIb), where patients exhibit neurologic defects and hypogammaglobulinemia. Along with these gross manifestations however, is an intriguing resistance to viruses with glycan shields: most notably, HIV and influenza [8].
Drugs that interfere with host endoplasmic reticulum glucosidase activity have been used to reduce the infectivity of secreted virions [9]. Drugs that interfere with N-glycan processing have been proposed as ways to disrupt the morphogenesis of a broad spectrum of enveloped viruses [10]. Such drugs would also affect processing of N-glycans in host cells.
The effects of reducing or disabling expression of MOGS on the in vivo and ex vivo viability, robustness, and immunological properties of antigen-specific T-cells, and on the resistance of such T-cells to virus invasion and infection have not been previously reported. Thus, the capacity T-cell immunotherapies using such T-cells to treat cancer, viral diseases and other pathologies involving T-cells were not known.